Malignant tumors are a fatal disease threatening human beings. The global cancer reports published by the world health organization (WHO) in 2014 indicated that cancer patients are increasing rapidly. It is estimated that the morbidity will achieve 24 million cases by 2035. Moreover, almost half of the new cancer cases have occurred in Asia and most in China. While surgery, radiotherapy, chemotherapy and immunotherapy are the traditional modalities for treating cancer, these approaches have some limitations including side effects, poor response, so there is an urgent need to find novel alternative treatments. Photodynamic therapy (PDT) is an emerging therapeutic modality and has been approved in clinical application in the treatment of neoplastic diseases. The therapeutic process of PDT involves the following aspects: (1) The photosensitive drug (photosensitizer) is administrated to the subject orally or intravenously, and the photosensitizer will preferentially accumulate in the pathological tissues due to the metabolizing difference between the normal tissues and pathogenic tissues; (2) Employing a light with a specific wavelength to illuminate the target tissue to activate the photosensitizer; (3) The activated photosensitizer will transfer the energy to the surrounding molecules to generate cytotoxic radicals or radical ions (Type I mechanism); or the activated photosensitizer will transfer the energy to molecular oxygen, to generate singlet oxygen (Type II mechanism). Both pathways directly or indirectly result in the cell destruction or death, while the individual light or photosensitizer has little effect.
Compared with traditional treatments, PDT has many advantages such as safety, targeting ability, minimally invasive, and also rapid recovery. PDT can not only kill the tumor cells directly, but also initiates the antitumor immune system, and thus prevents tumor recurrence and metastasis. The unique characteristics of selectively attacking and killing tumor cells while having minimal or even no damage to the surrounding normal tissues, make PDT a promising treatment.
Additionally, based on the intrinsic fluorescence and selectively localizing ability of the photosensitizer, photosensitizer can also be used for medical diagnosis, known as photodynamic diagnosis (PDD). With the development of novel light sources, optical fiber and other related technologies, the indications for PDT have expanded from the superficial tumors to deep tissue tumors. PDT can also be used to treat some benign diseases, such as microbial infections. During recent years, the globally occurrence of infectious diseases caused by microorganisms, especially antibiotic resistant pathogens are increasing, which has become a great threat to human health. Similar to tumor cells, pathogenic microorganisms have similar properties including fast propagation and metabolism, and thus there is an urgent need for novel treatments to solve the problem of drug resistance. The unique action mechanism, prominent advantages and repeatability make PDT a promising alternative to treating infectious diseases.
However, the key element in effective PDT treatment is the photosensitizer used. An ideal photosensitizer should have a high quantum yield (QY)-including singlet oxygen quantum yield (SOQY) and fluorescence quantum yield (FQY), strong absorption in the near infra-red region (600-900 nm), good selectivity, low dark toxicity, stable composition, well-defined structure, and easy preparation. Photofrin was the first photosensitizer approved by FDA, but it has many shortcomings, such as short wavelength absorption, complicated and unstable composition. The subsequently developed photosensitizers are mostly based on the tetra-pyrole structure, such as protoporphyrin IX (PpIX) and its prodrug Aminolevulinic acid (ALA) are approved in US and Europe, Temopofin is approved in Europe, Norway and Iceland, Sulphonated Aluminium Phtaalocyanine is approved in Russia, as well as some preclinically and clinically tested photosensitizers, such as Bacteriochlorins, Texafrins, Chlorin e6 and Purlytin. Although porphyrin-based photosensitizers have been developed rapidly, the structures of this class of compounds are relatively complicated, preparation and purification are difficult, industrious production is of high cost, and have relatively strong skin photosensitivity.
Phenothiazines are a type of nonpoyphyrin-based compounds with a unique structure and simple preparation. This type of compounds also have a stable composition, high quantum yield, weak dark toxicity, good tumor selectivity, long and strong wavelength absorption, and can act both in type I and type II photochemical pathways. Most of these compounds are positively charged and have good water solubility, which help reduce or avoid the possibility of aggregation in aqueous solution. In addition, although most of the photosensitizers are effective to Gram-positive bacteria in photodynamic antimicrobial trials, they usually demonstrate poor effects or even non-effective to Gram-negative bacteria. Phenothiazine compounds are effective against both Gram-positive and -negative bacteria because of their intrinsically cationic properties which can readily bind to the negative charged membrane through electronic interaction. For instance, methylene blue (MB)-a typical analog of phenothiazine compounds, has been used to photo-disinfect blood products, sterilize dental cavities, and kill micro-organisms, including human immunodeficiency virus (HIV), hepatits B and C. However, methylene blue also has limitations, such as low stability. Recently, Wainwright et al. successively reported the photodynamic effects of a series of MB analogs, new methylene blue (NMB) and dimethyl methylene blue showed better photoactivities against tumor cells and microorganisms than MB (1998, 2012). Hereafter, Stanley B. Brown reported series of symmetric and unsymmetric MB analogs, and a derivative named PPA904 with n-butyl side chain showed better photoactivity than MB, and it was also effective in photodynamical inactivation of Gram-positive and Gram-negative bacteria (2002, 2008). Clinical II trials using PPA904 for PDT treating chronic leg ulcers were completed, and it showed excellent therapeutic effect. Therefore, there is a need for novel potent non-porphyrin-based photosensitizers with excellent physiochemical and photodynamic properties. The phenothiazines of this invention, which have been shown to be surprisingly effective photosensitizers, fulfill this and other related needs.